This project involves clinical research in obsessive- compulsive disorder (OCD) directed towards (1) enhancement of our understanding of OCD pathogenesis, and (2) investigating potential new treatments for this major neuropsychiatric disorder. Our studies use pharmacological probes, neuroimaging, and transcranial magnetic stimulation to investigate pathophysiology in OCD and mechanisms underlying its pharmacological treatment. Other studies assess the relevance of neurotransmission-related candidate genes to OCD and to personality dimensions which are potentially relevant to the illness. Using the "paired-pulse" transcranial magnetic stimulation (TMS) technique first established as a probe of cortical physiology, we found that intracortical inhibition, thought to be GABA-modulated, was defective in OCD patients. This finding is interesting in view of preclinical data indicating important interactions between brain GABAergic and serotonergic circuits and our preliminary evidence that gabapentin, a GABA-modulator, improves the response to serotonin reuptake inhibiting antidepressants in OCD. A controlled study of gabapentin augmentation, which includes TMS measures to determine if corticol excitability changes after gabapentin treatment, is underway. Impaired intracortical inhibition, which is also found in the OCD-related illness, Tourette's Syndrome, could be due to intracortical dysfunction or basal ganglia pathology. Our preliminary finding of structural abnormalities in the basal ganglia of OCD patients using magnetic resonance relaxometry is consistent with theories of striatal pathology in OCD. In an MRI volumetric study we are also testing the hypothesis that basal ganglia abnormalities are associated with OCD by performing volumetric studies of the basal ganglia in OCD. Our most recent neuroanatomical approach to OCD is a collaborative project using diffusion tensor MRI to assess the therapeutic relevance of changes in white matter anatomy after gamma-knife capsulotomy in treatment-refractory patients performed by our colleagues at Brown University. Finally, we are actively pursuing associations between candidate genes affecting central neurotransmission and OCD. Some candidate genes of potential interest, such as functional genetic variants in the promoter regions of genes affecting monoaminergic neurotransmission, are being identified in our ongoing studies of the genetics of anxiety- and depression-related personality dimensions. In one such dimensional phenotype study, we have recently found that the association between functional allelic variation in the serotonin transporter promoter region and heritable personality traits related to depression and anxiety that we had seen previously in a large, mainly male cohort was replicated in a large primarily female population sample. Preliminary analysis suggests an association between allelic variation at the serotonin transporter promoter region polymorphism and OCD, some of the first evidence that genetic differences in serotonin systems may predispose to OCD.